Distinct metabolic adaptation of liver circadian pathways to acute and chronic patterns of alcohol intake

Gaucher, Jonathan; Kinouchi, Kenichiro; Ceglia, Nicholas; Montellier, Emilie; Peleg, Shahaf; Greco, Carolina; Schmidt, Andreas; Forné, Ignasi; Masri, Selma; Baldi, Pierre; Imhof, Axel; Sassone–Corsi, Paolo

doi:10.1073/pnas.1911189116

Cited by 41 publications

(33 citation statements)

References 78 publications

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“…We observed arrhythmic mRNA levels of Srebf1 /SREBP-1c in livers of alcohol-fed Fl/Fl mice, leading to disrupted diurnal rhythms in mRNA levels for the SREBP-1c target genes Acaca /ACC1 and Fasn . Gaucher et al (2019) also found that Srebf1 /SREBP-1c and targets were repressed by 6 weeks of alcohol consumption. While it might be predicted that Srebf1 /SREBP-1c mRNA levels would be elevated in alcohol-induced fatty liver, You et al (2002) reported that alcohol increases de novo lipogenesis post-transcriptionally by increasing translocation of the mature form of SREBP-1c protein into the nucleus.…”

Section: Discussionmentioning

confidence: 77%

Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver

et al. 2020

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Heavy alcohol drinking dysregulates lipid metabolism, promoting hepatic steatosis-the first stage of alcohol-related liver disease (ALD). The molecular circadian clock plays a major role in synchronizing daily rhythms in behavior and metabolism and clock disruption can cause pathology, including liver disease. Previous studies indicate that alcohol consumption alters liver clock function, but the impact alcohol or clock disruption, or both have on the temporal control of hepatic lipid metabolism and injury remains unclear. Here, we undertook studies to determine whether genetic disruption of the liver clock exacerbates alterations in lipid metabolism and worsens steatosis in alcohol-fed mice. To address this question, male liver-specific Bmal1 knockout (LKO) and flox/flox (Fl/Fl) control mice were fed a control or alcohol-containing diet for 5 weeks. Alcohol significantly dampened diurnal rhythms of mRNA levels in clock genes Bmal1 and Dbp, phase advanced Nr1d1/ REV-ERBα, and induced arrhythmicity in Clock, Noct, and Nfil3/E4BP4, with further disruption in livers of LKO mice. Alcohol-fed LKO mice exhibited higher plasma triglyceride (TG) and different time-of-day patterns of hepatic TG and macrosteatosis, with elevated levels of small droplet macrosteatosis compared to alcohol-fed Fl/Fl mice. Diurnal rhythms in mRNA levels of lipid metabolism transcription factors (Srebf1, Nr1h2, and Ppara) were significantly altered by alcohol and clock disruption. Alcohol and/or clock disruption significantly altered diurnal rhythms in mRNA levels of fatty acid (FA) synthesis and oxidation (Acaca/b, Mlycd, Cpt1a, Fasn, Elovl5/6, and Fads1/2), TG turnover (Gpat1, Agpat1/2, Lpin1/2, Dgat2, and Pnpla2/3), and lipid droplet (Plin2/5, Lipe, Mgll, and Abdh5) genes, along with protein abundances of p-ACC, MCD, and FASN. Lipidomics analyses showed that alcohol, clock disruption, or both significantly altered FA saturation and remodeled Valcin et al.

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Section: Discussionmentioning

confidence: 77%

Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver

et al. 2020

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“…20 Another study has performed acute or chronic alcohol feeding in mice and has demonstrated that both acute and chronic alcohol drinking change profiles of hepatic circadian transcriptome, especially in sterol regulatory element-binding protein (SREBP) pathways in the liver, indicating the change of circadian rhythms by alcohol drinking. 21 Binge alcohol drinking increases serum levels of alcohol as well as endotoxin (LPS) in healthy individuals. 19 Zeitgeber time (ZT) is the standard notation in studies of the circadian cycle.…”

Section: Alcoholic Liver Diseasementioning

confidence: 99%

“…Alcohol drinking elevated expression levels of PER1 and decreased for CRY1 , and changed circadian oscillation patterns for CRY2 regardless of working time . Another study has performed acute or chronic alcohol feeding in mice and has demonstrated that both acute and chronic alcohol drinking change profiles of hepatic circadian transcriptome, especially in sterol regulatory element‐binding protein (SREBP) pathways in the liver, indicating the change of circadian rhythms by alcohol drinking . Binge alcohol drinking increases serum levels of alcohol as well as endotoxin (LPS) in healthy individuals .…”

Section: Functional Roles and Therapeutic Potentials Of Melatonin Andmentioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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“…The proteome and acetylome protocol was adopted from (Gaucher et al, 2019;Peleg et al, 2016a) For acetylome analysis equal concentrations of peptides were incubated with 45 µl anti-acetyllysine antibody (ImmuneChem) overnight at 4°C. Beads were washed 4x with PBS/Tween 0.1% and then 4x with PBS.…”

Section: Liver Proteome and Acetylome Sample Preparationmentioning

confidence: 99%

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

Mueller-Eigner

Sanz-Moreno

de-Diego

et al. 2020

Preprint

Self Cite

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Metabolic syndrome is widespread and negatively impacts healthy longevity but takes years to study in mammalian models, delaying translational applications. To address this, we characterized the unique polygenic "Titan" mouse (110 grams average) with a healthy lifespan of only 4 months that was generated by 45 years of breeding selection. Titan mice displayed increased plasma leptin, insulin, IL-6 and fasting triglycerides. Also, pancreatic fat cell accumulation and thymic medullary hyperplasia were detected in Titan animals. Liver transcriptome and proteome analysis demonstrated alterations in lipid metabolism, the methionine cycle, and cytochrome P450 regulation in Titan mice. Late dietary intervention in Titan mice reduced fat content and improved expression of genes involved in lipid synthesis and cytochrome P450 detoxification, altering the abundance of metabolites, including malonyl-CoA and dimethylglycine. Strikingly, late dietary intervention at 3 months of age almost doubled the healthy lifespan of Titan mice. This powerful model of metabolic disorders, systemic inflammation, and early aging will enable to provide uniquely rapid results for translational intervention.

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Distinct metabolic adaptation of liver circadian pathways to acute and chronic patterns of alcohol intake

Cited by 41 publications

References 78 publications

Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver

Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

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